Overall Program

History

A new investigative group was formed in 1994 to reconsider theories of local and remote organ injury.  Initially, the group was composed of the Director, Dr. Francis D. Moore, Jr., a complement expert, Dr. Herbert Hechtman, known for his expertise on mediators, Dr. Danny Jacobs, an expert in measuring tissue metabolism, and Dr. Michael Carroll, a complement expert with special competence in transgenic animals.  This Trauma Center Grant was funded in April 1995, and renewed competitively in 1998.  With the departure of Dr. Jacobs to Creighton University (subsequently to Duke) and the retirement of Dr. Hechtman from investigation, the Trauma Center Grant has recruited a new P.I, Dr. K. Frank Austen, of the Department of Allergy and Immunology, and his investigative group that has been so important in the delineation of mast cell biology.  Dr. Austen was Dr. Moore's research mentor during Dr. Moore's research fellowship.  The two have kept a close personal and scientific relationship since, over some twenty years.  Dr. Austen and Dr. Carroll have also had a long-standing collaborative effort over this period. 

 

PROJECT I: THE CORE COMPONENT OF THE TRAUMA CENTER

Administrative Core: (PI: Francis D. Moore, Jr., M.D.)   This is the central coordinating agency of this Trauma Center Grant.  It functions to ensure optimal utilization of resources with a broad system of budgetary management and scientific oversight.  In addition this Core carries out the function of outreach scientifically to the institution and to investigators outside the institution, through this Home Page, and through continuation of a resident research paper competition, and the designation of funds for scientists who visit the Trauma Laboratories or for our scientists to visit other laboratories to further the progress on the central hypothesis.

Staff:
Francis D. Moore, Jr., M.D., Principal Investigator
Herbert B. Hechtman, M.D., Emeritus Investigator
Jan Rounds, B.S., Admin Manager
Sean Oakes, B.S., Senior Technician

 

I/R Models Animal Core: (PI: Francis D. Moore, Jr., M.D.)  The I/R Models Animal Core provides uniform and prompt access of all Projects in the Trauma Center to the same murine reperfusion injury models and to an equivalent model of rat reperfusion injury.  Additional support for other Projects is provided through the performance of complement assays.  In this manner the Projects are united in the study of exactly the same injury produces by a central investigative service.

Staff:
Francis D. Moore, Jr., M.D., Principal Investigator
Sean Oakes, B.S., Senior Technician
Kohei Wakatsuki, M.D., Ph.D., Research Fellow
Jie Wei, Ph.D., Research Fellow

 

Transgenic Animal Core A: (PI: Michael C. Carroll, Ph.D.)  Mouse models have proven very effective in clarifying our understanding of human disease.  In particular, the development of mice bearing transgenes or mutations in which specific loci are silenced have led to identification of the IgM natural antibody and complement in induction of ischemia-reperfusion injury.  The goal of the Animal Core is to extend the studies by continuing to maintain and breed mice bearing specific deficiencies in C3, C4 and Cr2, and to generate new strains of mutant mice in which the immunoglobulin loci are modified using a gene targeting approach.  Both the complement deficient and the new strains of immunoglobulin mutant mice are critical for continuation of the study of the pathogenesis of I/R injury and will be shared among the different projects.

Staff:
Michael C. Carroll, Ph.D., Principal Investigator
Minghe Ma, Ph.D., Senior Research Associate
Elisabeth Carroll, D. Pharm., Senior Research Associate
Melissa Turman, Ph.D., Research Fellow
Sydney Lavoie, Animal Technician

 

Mast Cell/MC Mediators Animal Core: (PI: K. Frank Austen, M.D.) This animal core provides the mice necessary to study the role of the mast cell (MC) and its mediators in the local and remote injury that occurs following ischemic-reperfusion in either the skeletal muscle or in the intestine.  These studies use numerous spontaneous and genetically engineered mice lacking specific cells or mediators implicated in the local tissue and remote lung injury associated with ischemia-reperfusion in the skeletal muscle or intestine.  It also provides the support for investigating the interaction between the MC, the complement system and natural IgM, all of which are implicated in the pathobiology of ischemia-reperfusion.  Finally it provides support to define the mechanism of preconditioning protection against ischemia-reperfusion injury.

Staff:
K. Frank Austen, M.D., Principal Investigator
Michael F. Gurish, Ph.D., Co- Investigator
Tatiana Jones, M.D., Ph.D., Co-Investigator
Hamed Sadeghipour, M.D., Research Fellow 

Clinical Core: (PI: Selwyn Rogers, M.D., M.P.H.) The clinical core will provide tissue harvesting, human peritoneal lymphocytes, human subject recruitment, and protocol management as well for continuous availability of a mouse xenografted with human tissue.

Staff:
Selwyn Rogers, M.D., M.P.H., Principal Investigator
Dennis Orgill, M.D., Ph.D., Co-Investigator
Hamed Sadeghipour, M.D., Research Fellow

In summary, the Trauma Center Core provides transgenic animals, common animal models, human tissue and lymphocytes, and shared personnel support for study of problems related to the trauma patient.  The provision of mice which are transgenic in complement, transgenic in a variety of mast cell populations or functional components are provided by Dr. Austen's project.  Ready access to reproducible murine models of skeletal or mesenteric ischemia and reperfusion are provided in the Animal Model Core.  The technical, organizational, and administrative support of the Core makes possible the high degree of integrated effort of all the involved investigators.  The Core also organizes and tracks all group activities, as well as provides the Outreach to widen the Harvard Trauma Research Community.  The Administrative Core interacts with the national and international community through its web page. 

 

 

PROJECT II - THE ROLE OF NATURAL ANTIBODY IN REPERFUSION INJURY (Principal Investigator: Michael C. Carroll, Ph.D.)

Ischemia-reperfusion injury (I/R) represents inflammatory injury to the endothelium and underlying parenchymal tissues following reperfusion of hypoxic tissues.  This general syndrome is responsible for both acute and chronic injury to various tissues including the myocardium, central nervous system, hind limb and intestine.  Studies in rodent models implicate the complement system a a major mediator of injury.  Serum natural IgM is also critical in the induction of injury in two distinct tissues for activation of complement.  A universal mechanism that would explain these observations is that the hypoxic endothelium expresses neo-antigens that specifically bind natural IgM leading to activation of the classical pathway of complement and the  inflammatory response.  This project will test this hypothesis.  The proposed study is important as it will not only provide important reagents and murine models for furthering our understanding of the etiology of ischemia reperfusion injury but hopefully lead to the identification of a therapeutic approach to intervene in this major disorder of humans.

Staff:
Michael C. Carroll, Ph.D., Principal Investigator
Minghe Ma, Ph.D., Senior Research Associate
Elisabeth Carroll, D. Pharm., Senior Research Associate
Melissa Turman, Ph.D., Research Fellow
Sydney Lavoie, Animal Technician

 

PROJECT III - MAST CELL/MAST CELL MEDIATORS IN AUTOLOGOUS INFLAMMATORY INJURY (Principal Investigator: K. Frank Austen, M.D.)

An episode of ischemia followed by reperfusion such as occurs in traumatic injury, certain surgical procedures and various pathological conditions, results in injury in the local tissue and remote injury in the lungs as well.  Three components of the innate immune system have been implicated in the injury, natural IgM, the complement system and mast cells (MC).  These studies will initially focus on defining the role of the MC and its mediators in injury (both local and remote)  following ischemia in the skeletal muscle and contrast that with the injury that occurs following ischemia in the intestine.  The project will next define the interaction of the MC with the other innate immune system components in order to define the interaction, if any, between these different pathways.  These studies will make use of the knowledge and resources provided by the other parts of this program to define the aspects of interdependence and independence among the three components in producing the local and remote injury following ischemia in these two different tissues.  Lastly, using the knowledge gained in these studies, the mechanism of protection of preconditioning will be explored in order to distinguish whether this short period of ischemia is protective due to desensitization, exhaustion of a critical mediator(s) or via some other mechanism.  From these studies, a better understanding of the role of and interaction between the different innate immune system components will be achieved which will allow better interventions to prevent these injuries. 
Staff:
K. Frank Austen, M.D., Principal Investigator
Michael Gurish, Ph.D., Co-Investigator
Tatiana Jones, M.D., Ph.D., Co-Investigator
Wei Xing, M.D., Ph.D., Co-Investigator
Juying Lai, Technician
Hamed Sadeghipour, M.D., Research Fellow


PROJECT IV- IGM-BINDING EPITOPES IN INJURED TISSUE (Principal Investigator: Francis D. Moore, Jr., M.D.)

Project IV seeks to develop the finding that a single clone of murine IgM is pathogenic for intestinal reperfusion injury in antibody-deficient animals.  The first aim will be to determine whether this antibody binds to definable antigens in murine tissue, whether injured or not.  This investigation may lead to discovery of the identity of the murine antigen.  In parallel, studies of human peritoneal B lymphocytes will be initiated in an attempt to determine whether the products of these cells have activity which is similar to the activity of the monoclonal IgM.  Finally, support with histochemistry and complement assays will be given to other Projects within the Trauma Center.


Staff:
Francis D. Moore, Jr., M.D., Principal Investigator
Kohei Wakatsuki, M.D., Ph.D., Research Fellow
Jie Wei, Ph.D., Research Fellow 
Hamed Sadeghipour, M.D., Research Fellow
Sean Oakes, B.S., Senior Technician
Arianne Soleymanloo, B.S., Research Assistant